Inflammation is characterized by redness, swelling, heat and pain. These symptoms result from capillary dilation, leading to accumulation of fluid (edema) and migration of phagocytic leukocytes. Inflammatory states may be acute or chronic. For a general review of inflammation, see Fundamental Immunology, 3rd Edition, W. E. Paul (ed.), Raven Press, New York, N.Y., 1993, Chapter 29.
Inflammation plays a critical role in elimination of foreign substances. Generally, recognition components of the host's immune system bind to epitopes of the foreign matter, activating an amplification system that includes the complement cascade, cytokines, the coagulation cascade, lipid mediators and amines produced by mast cells. These activated systems and components alter blood flow, increase vascular permeability, augment adherence of circulating leukocytes to vascular endothelium, promote migration of leukocytes into tissues, and stimulate leukocytes to destroy the foreign substance. If the foreign matter is not eliminated by mononuclear phagocytes, such elimination occurs in tissue spaces and is performed by polymorphonuclear leukocytes (neutrophils and eosinophils), monocytes or cytotoxic lymphocytes that are recruited from the blood.
Elimination of foreign antigens does not generally produce clinically apparent inflammation. A clinical inflammatory state may occur if a large amount of foreign matter is present, if the antigen is present in an unusual location, or if the antigen is difficult to digest. Inflammation may also be a symptom of certain diseases, such as rheumatoid arthritis, autoimmune diseases, or acquired immunoregulatory abnormalities.
Platelet activating factor (PAF) is a phospholipid mediator of the above-noted antigen elimination/inflammatory process. Platelets produce a group of platelet-activating factors (PAFs) that are acetyl-alkylglycerol ether analogs of phosphatidylcholine. These PAFs cause platelet aggregation, phagocyte chemoattraction, stimulation of lysosomal enzyme release, and reactive oxygen product formation by neutrophils, eosinophils and macrophages. Leukocytes can also produce PAFs in response to inflammatory mediators, leading to increased vasopermeability, vasodilation and bronchoconstriction. In normal circumstances, PAF is an effective bioactive mediator of a host's response to routine physiological stimuli, such as destruction of foreign substances. However, in certain situations and diseases, PAFs may lead to pathologies (such as ischemia-reperfusion, necrotizing enterocolitis and asthma).when a response to a foreign body or self-antigen is turned upon the host itself. In the latter instance, an elevated concentration of PAF can initiate tissue injury associated with inflammation. Bazan provides a concise summary of PAF and its role in inflammation in Nature 374:501-02, 1995.
Accordingly, there is a need in the art for compounds that have anti-inflammatory activity. In addition, there is a need for active agents useful as lead compounds in drug development, and in particular for development of anti-inflammatory drugs, including drugs that selectively modulate the remodeling pathway of PAF synthesis.